Tachykinin receptor 1

TACR1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KSB, 2KS9, 2KSA
Identifiers
Aliases	TACR1, NK1R, NKIR, SPR, TAC1R, tachykinin receptor 1
External IDs	OMIM: 162323 MGI: 98475 HomoloGene: 20288 GeneCards: TACR1
Gene location (Human) Chr. Chromosome 2 (human) Band 2p12 Start 75,046,463 bp End 75,199,520 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6|6 C3 Start 82,379,315 bp End 82,537,085 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in canal of the cervix subcutaneous adipose tissue left uterine tube Achilles tendon smooth muscle tissue vagina tibial nerve putamen caudate nucleus gastric mucosa Top expressed in main bronchus mirror superior frontal gyrus trachea thyroid gland stomach neural tube axial skeleton cerebellar cortex duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function tachykinin receptor activity G protein-coupled receptor activity signal transducer activity protein binding substance P receptor activity Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane cell periphery cytoplasm cell surface dendrite cell body sperm flagellum sperm head sperm midpiece Biological process regulation of uterine smooth muscle contraction phospholipase C-activating G protein-coupled receptor signaling pathway response to pain detection of abiotic stimulus inflammatory response positive regulation of smooth muscle contraction signal transduction chemical synaptic transmission aggressive behavior acute inflammatory response positive regulation of leukocyte migration angiotensin-mediated drinking behavior learning or memory long-term memory regulation of blood pressure associative learning response to heat response to hormone response to ozone positive regulation of epithelial cell migration response to auditory stimulus response to organic cyclic compound regulation of smooth muscle cell migration sensory perception of pain positive regulation of synaptic transmission, cholinergic positive regulation of synaptic transmission, GABAergic response to estradiol response to progesterone response to nicotine operant conditioning positive regulation of renal sodium excretion ejaculation eating behavior positive regulation of vascular permeability response to morphine response to ethanol positive regulation of action potential positive regulation of blood pressure positive regulation of ossification positive regulation of vasoconstriction positive regulation of saliva secretion positive regulation of hormone secretion behavioral response to pain regulation of smooth muscle cell proliferation positive regulation of lymphocyte proliferation positive regulation of epithelial cell proliferation positive regulation of stress fiber assembly response to electrical stimulus smooth muscle contraction involved in micturition positive regulation of uterine smooth muscle contraction positive regulation of cytosolic calcium ion concentration tachykinin receptor signaling pathway positive regulation of flagellated sperm motility G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6869 21336 Ensembl ENSG00000115353 ENSMUSG00000030043 UniProt P25103 P30548 RefSeq (mRNA) NM_015727 NM_001058 NM_009313 RefSeq (protein) NP_001049 NP_056542 NP_033339 Location (UCSC) Chr 2: 75.05 – 75.2 Mb Chr 6: 82.38 – 82.54 Mb PubMed search
Wikidata
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The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

Properties

Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino acid sequence Phe-X-Gly-Leu-Met-NH₂, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.Substance P (SP) is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK₁ receptor.

Tachykinin NK₁ receptor consists of 407 amino acid residues, and it has a molecular weight of 58,000. NK₁ receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp-Arg-Tyr, which is responsible for association with arrestin and, Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins. The binding site for substance P and other agonists and antagonists is found between the second and third transmembrane domains. The NK-1 receptor is found on human chromosome 2 and is located on the cell's surface as a cytoplasmic receptor.

Distribution and function

The NK₁ receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells. The binding of SP to the NK₁ receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation. NK₁ receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression. Other diseases in which the NK₁ receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.

Mechanism

SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. When NK₁ receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the arachidonic acid mobilization via phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase. It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, it is known to sensitize neutrophils and enhance dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine and GABA. It is also known to secrete catecholamines and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E₂ and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output.

In combination therapy, NK₁ receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK₁ receptor antagonists. NK₁ receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT₃ antagonist treatments. It has been reported that centrally-acting NK₁ receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms.

Clinical significance

This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants. It is also a potential treatment for alcoholism and opioid addiction. In addition, it has been identified as a candidate in the etiology of bipolar disorder. Finally NK1R antagonists may also have a role as novel antiemetics and hypnotics.

Ligands

Many selective ligands for NK₁ are now available, several of which have gone into clinical use as antiemetics.

See also

• NK1 receptor antagonist
• Tachykinin receptor
• Discovery and development of neurokinin 1 receptor antagonists

Further reading

External links

• "Tachykinin Receptors: NK₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors,+Neurokinin-1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P25103 (Substance-P receptor) at the PDBe-KB.